Phosphorous prodrugs and therapeutic delivery systems using same

• US 5,627,165 A
• Filed: 09/23/1994
• Issued: 05/06/1997
• Est. Priority Date: 06/13/1990
• Status: Expired due to Fees

• Current Assignee: Drug Innovation & Design Incorporated
• Original Assignee: Drug Innovation & Design Incorporated
• Inventors: Glazier, Arnold
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US08/310,972
• Time in Patent Office: 956 Days
• Field of Search: 536/26.7, 536/26.71, 536/26.72, 536/26.74, 536/26.8, 536/26.9, 514/45, 514/46, 514/47, 514/49, 514/50, 514/51, 514/256, 514/261, 514/75, 514/143, 568/8, 568/13, 568/14
• US Class Current: 514/75
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07F 9/2429 of arylalkanols
• CPC Class Codes: C07F 9/4087 Esters with arylalkanols
• CPC Class Codes: C07F 9/4093 Compounds containing the structure P(=X)-X-C(=X)- (X = O, S, Se)
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The composition and methods of synthesis of phosphorus prodrugs are described. These methods can be used to convert negatively charged phosphorous bearing drugs into neutrally charged; lipid soluble prodrugs which are able to passively diffuse into cells and into tissues in vivo. Prodrugs for a variety of antiviral and anti-leukemic agents are described.

Claims

1. A prodrug compound for a parent drug, wherein the parent drug has the structure:

##STR31## wherein X is oxygen or sulfur;

n is 1 or 2; and

Y is defined by the remainder of the parent drug, with the proviso that the parent drug is not phosphoric acid;

wherein the prodrug compound has the structure;

##STR32## wherein X, n and Y are defined above; and

A is a benzyloxy derivative with one or more acyloxy groups in para or ortho positions relative to the phosphoester.

2. The prodrug of claim 1 wherein the benzylozy group is α

-substituted by a moiety which, upon hydrolysis of the phosphoester, will undergo in vivo an elimination reaction to form a carbon-carbon double bond at the α

-carbon.

3. The prodrug of claim 1 wherein the acyloxy group is a (--OCOR8) group, a (--O--CO₂ R8) group, a (--O--CONHCH₃) group or a (--O--CO--N(CH₃)₂) group, wherein R8 is alkyl, substituted or unsubstituted phenyl, or, together with the carboxylic acid group, is an amino acid, lactic acid, glycolic acid, glyceric acid or acetoacetic acid.

4. The prodrug of claim 1 wherein A is of the formula:

##STR33## wherein R₁, R₃, and R₆ are independently a (--O--CO--R8) group;

a (--O--CO₂ --R8) group;

an N-substitued amino carbonyl oxy;

a (--O--C(o)--NHCH3) group;

a (--O--C(O)--N(CH3)₂) group;

hydrogen;

a halogen;

a (--CO₂ R9) group;

a methyl group;

a hydroxymethyl group (HO--CH₂ --);

a hydroxyethyl;

a CO₂ --CO₂ R₁₁ group or a group which undergoes biotransformation in vivo to yield a hydroxy group;

R₂ and R₇ are independently hydrogen;

a (--CO₂ R10) group;

a methyl group;

a halogen;

a methoxy group;

(--O--CO--R8);

or a hydroxymethyl group (HO--CH₂);

R₄ and R₅ are independently hydrogen;

a methyl group;

methoxy-methyl (--CH₂ --O--CH₃), a (--CH₂ --CO₂ --R12) group;

a (--CH₂ --CO--CH₃) group;

a (--CH(CH3)--CO₂ --R12) group;

a (--CH₂ --CO--NH₂) group;

a (--CH₂ --NO₂) group;

or a (--CH₂ --SO₂ --CH₃) group;

R8 is alkyl, a substituted or unsubstituted phenyl group, or wherein R8 can also be selected such that R8--CO₂ H is an amino acid;

lactic acid;

glycolic acid;

glyceric acid;

or acetoacetic acid;

wherein R₉, R₁₀ , R₁₁ and R₁₂, independently are methyl, ethyl, phenyl, or benzyl; and

wherein at least one of the groups;

R₁, R₃ or R₆ is a (--O--CO--R8);

a (OCO₂ R8) group;

a (--O--CO--NHCH₃) group;

or a (--O--CO--N(CH₃)₂) group;

or a group which undergoes biotransformation in vivo to yield a hydroxy group.

5. The prodrug of claim 4, wherein the parent drug contains a monophosphate ester.

6. The prodrug of claim 4, wherein the parent drug contains a phosphodiester.

7. The prodrug of claim 4, wherein the parent drug contains a phosphonic acid or a phosphonate.

8. The prodrug of claim 5, wherein the parent drug is a nucleotide monophosphate drug.

9. A prodrug of claim 4, wherein the parent drug is selected from the group consisting of:

9-(2-phosphonylmethoxy-ethyl) adenine;

3'"'"'azido-dideoxythymidine 5'"'"'monophosphate;

2'"'"',3'"'"'-didehydro-2'"'"',3'"'"'dideoxythymidine 5'"'"'monophosphate;

2'"'"'3'"'"'dideoxyadenosine 5'"'"'monophosphate.

10. The prodrug of claim 4 wherein at least one of R₁, R₃ or R₆ is a (--O--CO--R8) group.

11. The prodrug of claim 10 wherein at least one of R₄ and R₅ is a (--CH₂ --CO₂ R₁₂) group, a (--CH₂ CO--CH₃) group;

a (--CH(CH₃)--CO₂ --R₁₂) group;

a (--CH₂ --CO--NH₂) group;

a (--CH₂ --NO₂) group;

or a (--CH₂ --SO₂ --CH₃) group.

12. The prodrug of claim 11 wherein R₄ is a (--CH₂ --CO₂ --R₁₂) group.

13. The prodrug of claim 12 wherein R₁₂ is methyl or ethyl.

14. The prodrug of claim 10 wherein R₁ is a (--O--CO--R₈) group.

15. The prodrug of claim 10 wherein R₈ is --(CH₂)_n --CH₃, isopropyl or isobutyl wherein n=0-18.

16. A prodrug of claim 4, wherein the structure of group "A" is selected from the group consisting of:

##STR34##

17. A prodrug of claim 16 wherein the parent drug is a nucleotide monophosphate.

18. A prodrug of claim 16 wherein the parent drug is selected from the group consisting of:

9-(2-phosphonylmethoxy-ethyl) adenine;

3'"'"'azido-dideoxythymidine 5'"'"'monophosphate;

2'"'"',3'"'"'-didehydro-2'"'"',3'"'"'dideoxythymidine 5'"'"'monophosphate;

2'"'"'3'"'"'dideoxyadenosine 5'"'"'monophosphate.

19. A prodrug of claim 16 wherein the group "A" has the following structure:

##STR35##

20. A prodrug of claim 19 wherein the parent drug is a nucleotide monophosphate.

21. A prodrug of claim 19 wherein the parent drug is selected from the group consisting of:

9-(2-phosphonylmethoxy-ethyl) adenine;

3'"'"'azido-dideoxythymidine 5'"'"'monophosphate;

2'"'"',3'"'"'-didehydro-2'"'"',3'"'"'dideoxythymidine 5'"'"'monophosphate;

2'"'"'3'"'"'dideoxyadenosine 5'"'"'monophosphate.

22. A prodrug of claim 4 of the following structure:

##STR36##

23. A prodrug of claim 22 of the following structure:

##STR37##

24. A prodrug of claim 22 of the following structure:

##STR38##

25. A prodrug of claim 4 of the following structure:

##STR39##

26. A prodrug of claim 25 of the following structure:

##STR40##

27. A prodrug of claim 4 of the following structure:

##STR41##

28. A prodrug of claim 4 of the following structure:

##STR42##

29. A prodrug of claim 4 of the following structure:

##STR43##

31. A process for delivering a phosphorous bearing drug into cells and through biological membranes by contacting the cells and biological membranes with a prodrug of claim 4.

32. A process of claim 31 where the parent drug is selected from the following groups:

a monophosphate ester compound;

a phosphodiester compound;

a phosphonate compound;

a phosphonic acid compound;

a phosphinic acid compound;

a nucleotide monophosphate compound.

33. A process of claim 32 where the parent drug is selected from the following group:

9-(2-phosphonylmethoxy-ethyl)adenine;

3'"'"'-didehydro-2'"'"',3'"'"'dideoxythymidine 5'"'"'monophosphate;

2'"'"'3'"'"'dideoxyadenosine 5'"'"'monophosphate.

34. A process for delivering a phosphorous bearing drug into cells and through biological membranes, by contacting the cells with a prodrug of claim 1.

35. A process of claim 33 wherein the prodrug is administered topically.

36. A method for treating herpesvirus infection in a mammal in need thereof comprising administering a prodrug of claim 1 in a pharmaceutically acceptable carrier wherein the parent drug is an antiviral agent.

37. The method of claim 36 wherein the prodrug is administered topically.

38. The method of claim 36 wherein the parent drug is 9-(2-phosphonyl methoxyethyl) adenine.

30. A prodrug compound for a phosphate or phosphonate bearing parent drug which is a mono or diester of the phosphate or phosphonate bearing parent drug wherein the prodrug is degraded to the parent phosphorous bearing drug by an elimination reaction to form a carbon-carbon double bond;

and wherein the elimination reaction is triggered by the spontaneous or enzymatic unmasking of a strongly electron donating group.